Submissions for variant NM_001368894.2(PAX6):c.664C>T (p.Arg222Trp)

dbSNP: rs757259413

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413794	SCV000490693	pathogenic	not provided	2022-08-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016)
Eurofins Ntd Llc (ga)	RCV000413794	SCV000708115	likely pathogenic	not provided	2017-05-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000984424	SCV001430017	pathogenic	Aniridia 1	2020-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388984	SCV001590181	pathogenic	Aniridia 1; Irido-corneo-trabecular dysgenesis	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp). This variant is present in population databases (rs757259413, gnomAD 0.0009%). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372441). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAX6 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002463362	SCV002757803	pathogenic	Foveal hypoplasia 1; Irido-corneo-trabecular dysgenesis	2022-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529567	SCV004107619	pathogenic	PAX6-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic.
Wessex Regional Genetics Laboratory, Salisbury District Hospital	RCV000984424	SCV001055779	likely pathogenic	Aniridia 1	2019-08-15	no assertion criteria provided	clinical testing